There is no admission that the background art disclosed in this section legally constitutes prior art.
Although a number of treatments are available to treat the symptoms of mental disorders, relatively few efforts have focused on developing compounds that can improve cognitive function. While recent advances have been made in the understanding of the cholinergic nervous system and the receptors therein, there is still a need to develop compositions which would have a positive effect on a subject's cognitive functions.
One avenue of research being pursued involves cholinergic receptors which are proteins embedded in the cell membrane that respond to the chemical acetylcholine. Cholinergic receptors are subdivided into the nicotinic and muscarinic receptor families. Muscarinic receptors mediate a variety of physiological responses to the neurotransmitter acetylcholine in the central and peripheral nervous systems.
The muscarinic receptors represent a family of five subtypes. One subtype, M1 muscarinic receptors, plays a role in learning and memory function in the brain and regulates gastric acid secretion in the stomach. While an M1 agonist profile could provide efficacy in a broad range of symptomatic domains including enhancement of cognitive function, the development of selective muscarinic agonists has been hindered by the high degree of homology among the five receptor subtypes.
It is difficult to predict whether a muscarinic agonist will have a beneficial result. Efforts to develop muscarinic agonists for the treatment of neurological disorders have been hampered by the high degree of amino acid homology within the binding pocket of muscarinic receptors. While many compounds have been developed with reported selectivity, relatively few compounds have been identified that selectively activate M1 and/or M4 receptors. This is a particular concern in developing treatments that will enhance cognitive function, rather than only ameliorate functional deficit or impairment.
One of the co-inventors herein has developed different muscarinic agonists, which are claimed in U.S. Pat. Nos. 5,403,845; 5,175,166; 5,726,179; 6,096,767; 6,211,204 B1; 6,369,081 B1; 6,376,675 B2; and 6,602,891 B2; and in PCT patent applications Nos. WO/2007/075397 claiming priority to U.S. Ser. No. 60/754,529); PCT/US08/003637 (claiming priority to U.S. Ser. No. 60/919,800), which are expressly incorporated herein by reference. Also, muscarinic agonists are claimed in U.S. Pat. No. 5,618,818 which is owned by the same assignee as herein.
However, to date, there are no pharmacological agents that specifically target muscarinic receptor subtypes, leaving unanswered whether activation of muscarinic receptor subtypes enable cognitive flexibility.
In view of the foregoing, it would be desirable to provide muscarinic agonists that result in the selective activation of muscarinic receptors, particularly so that undesirable side effects are minimized during treatment.
Thus, there is a need for muscarinic agonists with activity at M1 receptors which then would useful in the treatment of Alzheimer's disease and schizophrenia, and other cognitive impairment disorders.
There is also a need for treatments that activate M1 receptors which enhance memory function and the various domains of cognitive flexibility.